GENOME/2014/184986-Revised Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin.
GENOME/2014/184986-Revised Spatial enhancer clustering and regulation of enhancer-proximal genes by cohesin.
复制标题
DOI：
--
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Elizabeth Ing-Simmons;Vlad C. Seitan;André J. Faure;Paul Flicek;Thomas;Carroll;J. Dekker;A. Fisher;B. Lenhard;M. Merkenschlager
中科院分区：
文献类型：
--
作者：
Elizabeth Ing-Simmons;Vlad C. Seitan;André J. Faure;Paul Flicek;Thomas;Carroll;J. Dekker;A. Fisher;B. Lenhard;M. Merkenschlager
.除了在细胞周期中介导姐妹染色单体凝聚外，凝聚素复合物还与CTCF和活性基因调控元件相关联，以在其结合位点之间形成长程相互作用。全基因组染色体构象捕获表明，粘着蛋白在间期基因组组织中的主要作用是介导结构染色体区室内的相互作用，而不是指定区室本身。然而，目前还不清楚如何cohesin介导的相互作用有助于基因表达的调控。我们已经发现CTCF和粘附素的结合在增强子处高度富集，特别是在小鼠胸腺细胞中的增强子阵列或“超级增强子”处。使用本地和全球的染色体构象捕获，我们表明，增强子元素不仅在线性序列，而且在3-D，空间增强子聚类促进了凝聚。从非循环胸腺细胞中条件性删除cohesin保留了增强子位置、H3 K27 ac、H4 K4 me 1和增强子转录，但减弱了增强子之间的相互作用。有趣的是，约50%的去调节基因位于增强子元件附近，这表明粘附素通过增强子元件的空间聚集来调节基因表达。我们提出了一个模型的粘着蛋白依赖的基因调控增强子元素的空间聚类作为一个统一的机制，增强子-启动子的“连接”和“绝缘”。超增强子中基因的失调频率最高（493个重叠基因中有138个失调控，27.99%; P < 2.2 × 10 - 16），与超级增强子最近邻的基因表达量显著低于对照组（P <0.05）。（位于超级增强子旁边的447个基因中的30.65%或137个被去调节; P < 2.2 X 10 - 16，图1C）。这些数据表明，在胸腺细胞中，在常规增强子和超级增强子附近的基因的调节表达需要粘附素，并且约50%的失调基因表达事件由基因相对于增强子的定位引起。
. In addition to mediating sister chromatid cohesion during the cell cycle, the cohesin complex associates with CTCF and with active gene regulatory elements to form long-range interactions between its binding sites. Genome-wide chromosome conformation capture had shown that cohesin's main role in interphase genome organization is in mediating interactions within architectural chromosome compartments, rather than specifying compartments per se . However, it remained unclear how cohesin-mediated interactions contribute to the regulation of gene expression. We have found that the binding of CTCF and cohesin is highly enriched at enhancers and in particular at enhancer arrays or 'super-enhancers' in mouse thymocytes. Using local and global chromosome conformation capture we demonstrate that enhancer elements associate not just in linear sequence, but also in 3-D, and that spatial enhancer clustering is facilitated by cohesin. The conditional deletion of cohesin from non-cycling thymocytes preserved enhancer position, H3K27ac, H4K4me1 and enhancer transcription, but weakened interactions between enhancers. Interestingly, ~50% of deregulated genes reside in the vicinity of enhancer elements, suggesting that cohesin regulates gene expression through spatial clustering of enhancer elements. We propose a model for cohesin-dependent gene regulation where spatial clustering of enhancer elements acts as a unified mechanism for both, enhancer-promoter 'connections' and 'insulation'. The highest frequency of deregulation was found for genes positioned within super-enhancers (138 of 493 overlapping genes were deregulated, 27.99%; P < 2.2 x 10 -16 ) and genes that are nearest neighbors of super-enhancers (30.65% or 137 of 447 genes positioned next to super-enhancers were deregulated; P < 2.2 x 10 -16 , Figure 1C). These data indicate that cohesin is required for the regulated expression of genes near conventional enhancers and super-enhancers in thymocytes, and that ~50% of deregulated gene expression events are accounted for by the positioning of genes relative to enhancers.